Serotonin 5-HT₂ Receptors in Schizophrenia: A PET Study Using [¹⁸F]Setoperone in Neuroleptic-Naive Patients and Normal Subjects

OBJECTIVE: Several postmortem studies have reported a decreased density of serotonin 5-HT₂ receptors in the prefrontal cortex in schizophrenia. The purpose of this study was to investigate this in patients with schizophrenia by means of [¹⁸F]setoperone and positron emission tomography (PET) imaging. METHOD: Thirteen neuroleptic-free patients with schizophrenia, 10 of whom were also neuroleptic-naive, were compared with a group of 26 normal subjects in the same age range. The density of 5-HT₂ receptors was assessed with the use of [¹⁸F]setoperone and PET in standardized cortical regions of interest. RESULTS: Increasing age was associated with similar declines in 5-HT₂ receptors in all cortical regions in the patient group and in the normal comparison group. After control for the effect of age, there was no statistically significant difference between the patients and the comparison subjects in 5-HT₂ receptor density in any of the cortical regions. CONCLUSIONS: This study failed to find the decrease in 5-HT₂ receptors reported in postmortem studies of schizophrenia. The study had the power to detect a decrease of 25% or more in 5-HT₂ receptors, which was anticipated on the basis of the previous postmortem studies. Thus, a primary serotonergic abnormality in schizophrenia, if one exists, is either small or unlikely to be at the level of the 5-HT₂ receptors. This finding does not rule out a therapeutic role for 5-HT₂ antagonists in schizophrenia, but it does suggest that the therapeutic contribution is likely to be an indirect one.